The term “Parkinson's plus syndrome” covers several idiopathic diseases which are associated with the occurrence of symptoms which are Parkinson-like but that may be differentiated by diagnostic and clinical/pathophysiological means from Parkinson's disease.
The diseases classed as Parkinson plus syndrome (PPS) include multiple system atrophies (MSA), progressive supranuclear palsy (PSP), corticobasal ganglionic degeneration (CBGD) and dementia with Lewy bodies (DLB).
Multiple system atrophies subsume, in particular, Shy-Drager syndrome, olivopontocerebellar atrophy (OPCA) and striatonigral degeneration (SND). See Mark et al, Neurol Clin. 2001, 19(3): 607.
The assignment of Pick's disease, hemiparkinsonism and parkinsonism in Alzheimer's and ALS patients and the Westphal variant of Huntington's chorea to PPS is not uniform in specialist literature, but for the purposes of the present patent application, these diseases are considered to be subsumed under the term PPS in accordance with the classification used by Hobson et al,Can J Neurol Sci. 2003 March; 30 Suppl 1: p 2.
Common to the diseases subsumed under Parkinson's plus syndrome is the lack of, or rapidly diminishing, response to L-dopa or dopamine agonists and additional symptoms such as cerebellar or pyramidal signs, early or severe dementia plus speaking and swallowing disorders in the early phase (Mark 2001, supra; Gerlach et al, Die Parkinson-Krankheit, Springer, Vienna N.Y., 2003).
For an overview of differential-diagnostic criteria and classification of some symptoms for several Parkinson's plus syndromes and Parkinson's disease (also known as idiopathic Parkinson's syndrome, IPS), Table 1 is provided below.
TABLE 1Parkinson's plus syndromeMultiple system atrophySNDOPCACBDPSPIPSRigor/akinesia+++++/+++++/+++++/+++Cerebellar signs+++−−−Pyramidal signs−+++++−Postural+++++++instabilityDementia−−+++Oculomotor+(+)+++++disordersDysphagia−++++++Retrocollis−−−++−Sphincter++−−−disordersImpotence++++++SND: striatonigral degenerationOPCA: olivopontocerebellar atrophyCBD: corticobasal degenerationPSP: progressive supranuclear palsyIPS: idiopathic Parkinson's syndrome
Table 1 is based on Mark MH, Lumping and splitting the Parkinson plus syndromes: dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and corticalbasal ganglionic degeneration. Neurol Clin. 2001 August; 19(3): 607-27 . The table is also modified according to Gerlach M, Reichmann H, Riederer P, Die Parkinson-Krankheit, Springer Vienna N.Y., 2003.
Computed tomography is an important criterion when differentiating between IPS and PPS. Patients with IPS display normal dopamine receptor levels in the SPECT until the late stages, while PPS patients demonstrate an early loss of pre- and postsynaptic dopaminergic neurons, which is associated with an identifiable reduction in the density of dopamine receptors. PET analyses confirm a reduced L-dopa content and L-dopa metabolism in IPS patients (Gerlach et al., 2003, supra).
Due to the frequently absent or poor response to L-dopa, drug treatment for PPS is difficult and generally consists in a symptomatic therapy for specific individual symptoms, e.g. treatment for hypotension.
Dopamine receptor agonists are generally ineffective for the treatment of PPS (Mark, 2001, supra). In exceptional cases, there have been reports of a certain therapeutic success with individual dopamine agonists, although these effects appear to be substance-specific. For example, Wenning et al (Lancet, 2004, 3, 93) reported on the therapeutic success of bromocriptine in a trial with six patients, while a controlled trial with lisuride found no efficacy. Since it is known that the majority of dopamine agonists do not act on one sole dopamine receptor, but have a complex receptor profile (Newman-Tancredi, J Pharmacol Exp Ther 2002, 303, 805), the reason for the efficacy of bromocriptine could be the special features of the receptor profile or other not further characterised substance-specific properties.
Parkinson's plus syndrome is generally linked to a dopaminergic neurodegeneration in the substantia nigra (Mark, 2001, supra). Therefore, successful therapy could be expected from the use of effective neuroprotectives which inhibit the progressive degradation of dopaminergic neurons (Dawson and Dawson V L, Nat Neurosci. 2002 November; 5 Suppl: 1058).
Rotigotine [(−)5,6,7 ,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl] amino]-1-naphthol] is known from the prior art as a dopamine agonist and symptomatic therapy for Parkinson's disease.
WO 02/089777 describes, for example, the transdermal administration of rotigotine in Parkinson patients and the associated improvement in the UPDRS (Unified Parkinson's Disease Rating Scale) scores and this has also been described by other authors (Metman et al, Clin Neuropharmacol. 2001, 24(3):163; Mucke H A, Rotigotine Schwarz Pharma. IDrugs. 2003 September; 6(9):894; The Parkinson Study Group, Arch Neurol. 2003 60(12):1721).
The UPDRS score is an important tool for the diagnosis or treatment of patients with Parkinson's disease (Fahn S, Elton R L, Members of the UPDRS Development Committee (1987) Unified Parkinson's Disease Rating Scale. In: Fahn, S, C D Marsden, D B Calne, M Goldstein (eds) Recent Developments in Parkinson's Disease. Vol II. Macmillan Healthcare Information, Florham Park (N.J.), pp 153-163, 293-304). However, the UPDRS score only determines the effect of an active substance on the symptoms of Parkinson's disease. It does not provide any information as to whether an active substance influences the dopaminergic cell destruction at the root of the symptoms.
However, apoptotic processes play an important role in the pathogenesis of Parkinson's plus syndrome in particular with regard to the destruction of dopaminergic neurons. See, for example, Lev et al, Prog Neuropsychopharmacol Biol Psychiatry. 2003; 27(2): 245; Michel et al, Rev Neurol (Paris). 2002; 158 Spec no 1: p 24. In addition, as reported in Hirsch et al (Ann N.Y. Acad Sci. 2003; 991: 214), various other neurodegenerative processes are thought to have a decisive influence on the development of parkinsonism and Parkinson's plus syndrome.
Therefore, there is a desire for neuroprotective substances that are able to stop or even reverse dopaminergic cell destruction (Vila et al, Nat Rev Neurosci. 2003; 4(5): 365). Here, the MPTP model is considered to be predictive for the required neuroprotective properties (Dawson, 2002, supra; Eberhardt O, Schulz J B, Toxicol Lett. 2003, 139(2-3): 135).